Pore structures for reduced pressure aerosolization

ABSTRACT

A nozzle comprising a thin, flexible substantially planar polymeric film having a plurality of pores with structures allowing for generation of an aerosol at reduced extrusion pressure is disclosed. The pores can comprise at least two sections, or steps, in which the thickness of the membrane is reduced in stepwise fashion, or the pores can be tapered. Nozzles formed comprising pores having such structures permit aerosol generation at lower extrusion pressures, thereby allowing for decreased weight of aerosolization devices, increased efficiency, increased portability and increased battery life. The pore structures also allow for the use of thicker, more easily processed polymeric films in manufacturing while having a thinner, more efficient aerosolization area. The use of decreased extrusion pressures also results in increased uniformity in aerosol generation and improved reliability of other components.

FIELD OF THE INVENTION

[0001] This invention relates generally to devices and methods foraerosolizing formulations. More specifically, this invention relates toan aerosolization nozzle comprising a membrane having pore structuresfor reduced pressure aerosolization.

BACKGROUND OF THE INVENTION

[0002] Aerosolization is a desirable means for the delivery oftherapeutic or diagnostic agents. Aerosol delivery avoids the problemsassociated with other delivery methods such as oral administration orinjection. Injections are painful, present a risk of infection to thehealth-care provider from an inadvertent needle-stick, and createhazardous waste from the needle and syringe. Additionally, repeatedinjections can result in scarring. Oral administration must overcomeseveral obstacles to the delivery of agents, including the acidicenvironment of the stomach, the ability of the agent to pass through theof the intestinal wall, and first-pass metabolism of the agent by theliver. Aerosol delivery, on the other hand, allows the direct deliveryof agents to areas such as the nasal tract, the respiratory tract, orthe eye, as well as systemic delivery into the circulation byadministration to the respiratory tract and uptake into the circulation.

[0003] Currently available methods of generating and delivering aerosolsto the nasal and respiratory tract include metered-dose inhalers, drypowder inhalers and nebulizers. Available methods of delivering agentsto the eye include ointments and eye drops.

[0004] Co-owned U.S. Pat. Nos. 5,544,646; 5,718,222; 5,660,166;5,823,178; 5,709,202; and 5,906,202 describe devices and methods usefulin the generation of aerosols suitable for drug delivery. A drugformulation is forcibly applied to one side of a pore-containingmembrane so as to produce an aerosol on the exit side of the membrane.Aerosols containing particles with a more uniform size distribution canbe generated using such devices and methods, and can be delivered toparticular locations within the respiratory tract.

[0005] However, the high pressures which must be used to generateacceptable aerosols present significant limitations on aerosolizationdevices. Sufficient power must be provided by the devices to generatethe desired pressure. Larger power sources increase the weight of thesedevices, and thereby decrease the mobility of patients. In portabledevices, battery life is also decreased by higher power needs.Additionally, higher pressures increase the required pressure tolerancesof other system components. Elevated pressures may also lead tovariability in aerosol quality.

SUMMARY OF THE INVENTION

[0006] The present invention provides aerosolization nozzles for use inaerosolization devices for delivering a formulation, which may contain adrug(s) and/or diagnostic agent(s), to an individual. Aerosolizationnozzles of the present invention comprise a membrane having porestructures that are particularly well suited for aerosolization atreduced extrusion pressures. By decreasing the pressure which must besupplied to generate a uniform aerosol, such nozzles allow for decreasedweight of the delivery devices and increased patient mobility. Batterylife is thereby increased, leading to further increases in patientmobility. Additionally, at lower pressures the required tolerances ofother system components is reduced. Reduced pressure duringaerosolization may also result in increased aerosol uniformity andimproved reliability of such aerosolization devices.

[0007] The membrane has an entrance side to which formulation is appliedunder pressure, and an exit side, from which aerosol is extruded, and anozzle area, which has a plurality of pores penetrating the thickness ofthe membrane. The membrane is preferably flexible. Each pore has anentrance diameter (or cross-sectional area) and an exit diameter (orcross-sectional area). The exit aperture of the pores in the nozzle isof a size sufficient to generate an aerosolized particle of the desiredsize.

[0008] The pore structures of the present invention have an increasedentrance diameter to exit diameter ratio when compared to those inpreviously described aerosolization nozzles. Generally, the ratio is atleast 10:1. In some embodiments, this ratio is 15:1. In otherembodiments, this ratio is 25:1 or greater.

[0009] These specialized pore structures (“reduced-pressureaerosolization pores”) confer a major advantage when formed inaerosolization membranes, in that the reduced pressure required to forcea flowable formulation through a nozzle comprising these specializedpores such that an aerosol is generated is significantly reduced. Thus,in some of these embodiments, the pressure required to force aformulation through the pores, such that an aerosol is generated in anacceptably short period of time, is less than about 500 pounds persquare inch (psi), generally less than about 400 psi, usually less thanabout 300 psi, down to about 200 psi or less.

[0010] The cross-sectional profile of the pores can be discontinuous(i.e., multi-step), or continuous, (i.e., tapered). When thecross-sectional profile of a pore is discontinuous, the diameter and/orcross-sectional area of a given pore step is reduced in a step-wisefashion, relative to the preceding pore step. When the cross-sectionalprofile of a pore is tapered, the diameter from the entrance side to theexit side decreases in a substantially continuous fashion, i.e., thereis a gradual diminution of diameter of the pore from the entrance sideto the exit side.

[0011] One aspect of the invention is a nozzle for aerosolizing aformulation for respiratory delivery, said nozzle comprising a membranehaving about 10 to about 1,000 reduced-aerosolization pressure pores persquare millimeter, said pores having an average relaxed exit aperturediameter of from about 0.5 to about 5 μm and are spaced at a distance offrom about 30 to about 70 μm apart from each other.

[0012] In yet another aspect of the invention, a nozzle is providedwherein the pores are incompletely formed so that, upon administrationof pressure to the entrance side of the film, the exit aperture isformed by bursting outward the exit side of the pores, thereby formingan elevated area preventing liquid intrusion into the exit aperture.

[0013] In a further aspect of the invention, a strip containing multiplenozzle areas comprising reduced-pressure aerosolization pores isprovided.

[0014] In a further aspect of the invention, a container is providedwhich comprises at least one wall which is reversible collapsible uponapplication of a force, and which includes at least one opening leadingto an open channel, at the end of which is a nozzle of the invention.The container can contain a flowable formulation which, upon applicationof a force to the collapsible wall, is forced through the channel andthe nozzle, whereupon an aerosol is generated. The invention furtherprovides a package comprising a plurality of such containers.

[0015] In another aspect, an aerosolization device comprising a nozzleof the invention is provided. In preferred embodiments, the device isprovided as a disposable package.

[0016] These and other objects, aspects, features, and advantages willbecome apparent to those skilled in the art upon reading the disclosurein combination with the figures forming a part hereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]FIG. 1 is a scanning electron micrograph of a pore formed viasingle-step laser ablation for a “standard” nozzle. Dimensions are givenin micrometers.

[0018]FIG. 2 is a schematic drawing of a two-step pore formed viamulti-step laser ablation.

[0019]FIG. 3 is a scanning electron micrograph of a two-step pore formedvia multi-step laser ablation. Dimensions are given in micrometers.

[0020]FIG. 4 is a scanning electron micrograph of a pore formed using agrayscale process. Dimensions are given in micrometers.

[0021]FIG. 5 is a scanning electron micrograph of a pore formed using adithering process. Dimensions are given in micrometers.

[0022]FIG. 6 is a cross-sectional view of a container of a preferredembodiment of a container of the invention.

[0023]FIG. 7 is a top plan view of a disposable package of theinvention.

[0024]FIG. 8 is a cross-sectional view of a portion of a disposablepackage of the invention.

[0025]FIG. 9 is a cross-sectional view of a container used in a channelof an aerosol delivery device.

[0026]FIG. 10 is a cross-sectional view of an aerosol delivery device ofthe invention having a multidose container and a ribbon of lowresistance filters and a ribbon of porous membranes.

[0027]FIG. 11 is a cross-sectional view of an aerosol delivery device ofthe invention having a multidose container and single ribbon having bothinterconnected low resistance filters and nozzles comprised of porousmembranes.

[0028]FIG. 12 is a cross-sectional view of an aerosol delivery device ofthe invention.

[0029]FIG. 13 is a cross-sectional view of an aerosol delivery device ofthe invention loaded with a cassette.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The invention provides improved nozzles comprising a membranehaving pores of small, uniform size for aerosolizing any type of drug ordiagnostic agent that permits the generation of uniform aerosols atreduced pressures as compared with previous nozzles. The membranes havean entrance side to which formulation is applied under pressure, and anexit side, from which the aerosol is released. The small exit aperturesizes required to generate aerosolized particles suitable for delivery,e.g., to the lung, also require high extrusion pressures to force aliquid formulation through the pores in the nozzle. In previousaerosolization nozzles, the required pressure to extrude a liquidformulation through a nozzle area having pores with an entrance diameterto exit diameter ratio of about 5-6 were in the range of about 650 toabout 750 psi. The pressure required for aerosolization from a porehaving a given exit aperture size decreases with increasing entranceaperture size. Thus, increasing the entrance aperture size relative tothe exit aperture size (other factors being equal) reduces the pressureneeded for aerosolization and thereby improves system performance.

[0031] In the present invention, the pores of the membrane havestructures that allow extrusion of a flowable formulation at reducedpressures, usually less than about 500 psi, generally in the range ofabout 200 to about 400 psi or less, wherein an aerosol is generated.This is achieved by generating pores having entrance diameter to exitdiameter ratios about 10:1, about 25:1, or greater.

[0032] The pores can have a discontinuous, step-wise, cross-sectionalprofile, or a continuous, tapered, cross-sectional profile. The poresare formed so as to have a relatively high entrance aperture sizerelative to exit aperture size. Nozzles formed in this way allow forimproved handling of the nozzle material during manufacturing andincrease the reliability of aerosolization devices incorporating them byoperating at lower pressures. The present invention providesaerosolization nozzles comprising these membranes, as well as methods ofcreating such pore structures

[0033] A method of generating an aerosol from such nozzles is alsoprovided. The devices used in conjunction with the present invention canbe hand-held, self-contained, highly portable devices which provide aconvenient means of delivering drugs or diagnostic agents to a patient.Because of decreased power needs for aerosolization, the devices can belighter and have increased battery life, leading to improved patientmobility.

[0034] In general, an aerosol for respiratory or ocular delivery isgenerated from a drug or diagnostic agent formulation, preferably aflowable formulation, more preferably a liquid, flowable formulation.The drug or diagnostic agent formulation can be contained within amultidose container or within a container portion of a disposablepackage, where the container of the disposable package has at least onesurface that is collapsible. The aerosol is generated by applyingpressure of 500 psi or less, preferably 400 psi or less, more preferably300 psi or less, down to about 200 psi, to the collapsible containersurface, thereby forcing the contents of the container through a nozzlecomprised of a porous membrane, such that an aerosol is generated. Theporous membrane may be rigid or flexible. Preferably the porous membraneis flexible so that upon application of the pressure required to aerosolthe formulation, the nozzle's porous membrane becomes convex in shape,thus delivering the aerosolized drug or diagnostic agent into the flowpath of the delivery device in a region beyond the flow boundary layer.

[0035] The amount of pressure needed to create an aerosol is determinedby several factors, including: (1) the ratio of the size of the entranceaperture to the exit aperture; (2) the size of the exit apertures; (3)the pore density, i.e., the number of pores per unit area of themembrane; (4) the amount of liquid being aerosolized; (5) the period oftime for aerosolization; (6) the viscosity of the liquid beingaerosolized; and (7) the pressure at the exit opening. Other factorssuch as temperature, atmospheric pressure, and humidity can also affectthe pressure needed to create an aerosol. Unless stated otherwise,factors other than the ratio of entrance to exit diameter will remainthe same and be standard.

[0036] The formulations for use in the present invention call includepreservatives or bacteriostatic type compounds. However, the formulationpreferably comprises a pharmaceutically active drug (or a diagnosticagent) and pharmaceutically acceptable carrier The formulation can beprimarily or essentially composed of the drug or diagnostic agent (i.e.,without carrier) if the drug or diagnostic agent is freely flowable andcan be aerosolized. Useful formulations can comprise formulationscurrently approved for use with nebulizers or for injections.

[0037] Further, the dispensing device of the present invention, whichcan be used to dispense a drug or diagnostic agent formulation accordingto the method of the invention, preferably includes electronic and/ormechanical components which eliminate direct user actuation of drugrelease. More specifically, where the device is used in respiratorytherapy, the device preferably includes a means for measuringinspiratory flow rate and inspiratory volume and sending an electricalsignal as a result of the simultaneous measurement of both (so that drugor diagnostic agent can be released at a preprogrammed optimal point)and also preferably includes a microprocessor which is programmed toreceive, process, analyze and store the electrical signal of the meansfor measuring flow and upon receipt of signal values within appropriatelimits sending an actuation signal to the mechanical means which causesdrug (or diagnostic agent) to be extruded from the pores of the nozzle'sporous membrane. Thus, since preferred embodiments of the devices usedin connection with the present invention include a means of analyzingbreath flow and a microprocessor capable of making calculations basedthe inhalation profile, the present invention can provide a means forrepeatedly (1) dispensing and (2) delivering the same amount of the drugor diagnostic agent to a patient at each dosing event.

[0038] Before the present nozzles (comprising membranes withreduced-pressure aerosolization pores), devices, containers,formulations and methods used in connection with such are described, itis to be understood that this invention is not limited to the particularmethodology, devices, containers and formulations described, as suchmethods, devices, containers and formulations may, of course, vary. Itis also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the present invention which will be limited onlyby the appended claims.

[0039] It must be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a formulation” includes mixtures of different formulations, referenceto “a pore” includes one or more pores, and reference to “the method oftreatment” and to “the method of diagnosis” includes reference toequivalent steps and methods known to those skilled in the art, and soforth.

[0040] Unless defined otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention belongs. Although any methodsand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methodsand materials are now described. All publications mentioned herein areincorporated herein by reference to describe and disclose specificinformation for which the reference was cited.

[0041] The publications discussed herein, supra and infra, are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

[0042] Definitions

[0043] The term “porous membrane” shall be interpreted to mean amembrane of material having any given outer parameter shape, butpreferably having a convex shape, or being capable of flexing into aconvex shape, wherein the membrane has a plurality of pores therein,which openings may be placed in a regular or irregular pattern. Thepores of the membrane have an entrance diameter larger than the exitdiameter, and the ratio of entrance:exit diameter is 5 or more to 1,preferably 10:1 or greater, more preferably 15:1 or greater, morepreferably 25:1 or greater. Preferably, the membrane has pores whichhave an unflexed diameter of their exit aperture in the range of 0.25micron to 6 microns and a pore density in the range of 1 to 1,000 poresper square millimeter for respiratory delivery. For ocular delivery, thepores have an unflexed diameter of their exit aperture in the range of0.5 microns to 50 microns, generally 1.0 to 25 microns, and a similarpore density. The porous membrane has a porosity of about 0.0005% to0.2%, preferably about 0.01% to 0.1%. In one embodiment, the porousmembrane comprises a single row of pores on, e.g., a large piece ofmembrane material. The pores may be planar with respect to the surfaceof the porous membrane material, or may have a conical configuration.

[0044] For purposes of the present invention, a porous membrane has anentrance side, to which formulation is applied under pressure, and anexit side, from which the aerosol is released. The membrane also has anozzle area, through which a plurality of pores passes. The pores passsubstantially perpendicularly through the thickness of the membrane,from the entrance side to the exit side. Each pore has an entrancediameter (or cross-sectional area) and an exit diameter (orcross-sectional area).

[0045] A “tapered pore”, as used herein, refers to a pore whose diameterand/or cross-sectional area decreases in a substantially continuousfashion from the entrance side to the exit side of the membrane.

[0046] A “stepped pore”, or “multistep pore”, as used herein, intends apore whose diameter and/or cross-sectional area decreases in a stepwise,discontinuous fashion from the entrance side to the exit side of theporous membrane through which it passes, in contradistinction to thesubstantially continuous, linear decrease in diameter characteristic ofa cone,-or the uniform diameter of a cylinder. A “stepped pore” refersto a pore which has at least one abrupt change in pore size, but thatabrupt change may be followed by a second smooth or continuous change insize, i.e., a pore step may be substantially cylindrical or cone-shaped.A “stepped pore” is a pore having a discontinuous cross-sectionalprofile, an example of which is shown schematically in FIG. 2. The term“pore step”, as used herein, refers to a segment of a multistep pore. Apore step passes through a portion, having a height h, of the membranematerial forming the nozzle, where b is less than the thickness of themembrane. The term “multistep pore” intends pores comprising two or moreof such steps. Each step is progressively, and discontinuously, reducedin diameter relative to the preceding step, going from the entrance toexit side of the membrane, ultimately resulting in an exit aperture sizecapable of producing aerosol particles of the desired size. Said anotherway, the diameter of the pore decreases abruptly from one step to thenext, going from the entrance side of the membrane to the exit side ofthe membrane. A given multistep pore is said to have a pore entranceaperture, i.e., the aperture on the entrance side of the membrane, and apore exit aperture, i.e., the aperture on the exit side of the membrane.Similarly, a given pore step is said to have a pore step entranceaperture and a pore step exit aperture. Each aperture has a size. If agiven aperture is roughly circular, then the size can be described asthe diameter. If a given aperture is irregularly shaped, or otherwisenon-circular, then the size can be described as the cross-sectional areaat the aperture. The position of a given pore step relative to anotherpore step can be expressed in terms of proximity to the entrance or exitside of the membrane. Thus, for example, the entrance aperture size of agiven pore step can be described in relation to the exit aperture sizeof the preceding “entrance proximal” pore step. The step of the poreimmediately adjacent to the exit side of the membrane from which theaerosol is produced is referred to as the “through-step” or “exit-step.”

[0047] As used herein, a “standard” nozzle is one that comprises“standard” pore structures, i.e., pore structures having an entranceaperture size to exit aperture size ratio less than 10:1. An example ofa standard pore structure is shown in FIG. 1.

[0048] The term “porosity” is used herein to mean a percentage of anarea of a surface area that is composed of open space, e.g., a pore,hole, channel or other opening, in a membrane, nozzle, filter or othermaterial. The percent porosity is thus defined as the total area of openspace divided by the area of the material, expressed as a percentage(multiplied by 100). High porosity (e.g., a porosity greater than 50%)is associated with high flow rates per unit area and low flowresistance. In general, the porosity of the nozzle is less than 10%, andcan vary from 10⁻% to 10% while the porosity of the filter is at least1%, and preferably it is at least 53% porous.

[0049] The terms “package” and “disposable package” are usedinterchangeably herein and shall be interpreted to mean a container ortwo or more containers linked together by an interconnecting meanswherein each container preferably includes one or more channels whichprovide for fluid connection from the container to a nozzle comprised ofa porous membrane, which nozzle is preferably not positioned directlyover the container, and wherein each container includes at least onesurface that is collapsible in a manner so as to allow the forceddisplacement of the contents of the container through a low resistancefilter and out the nozzle (without rupturing the container) in a mannersuch that the contents are aerosolized. There are at least two majorvariations of the package, depending on whether the drug can be stablystored in a liquid form or must be stored dry and combined with liquidimmediately prior to aerosolization.

[0050] The contents of each container preferably comprises aformulation, preferably a flowable formulation, more preferably aliquid, flowable formulation, which includes a pharmaceutically activedrug or a diagnostic agent. If the drug or diagnostic agent is notliquid and of a sufficiently low viscosity to allow the drug to beaerosolized, the drug or diagnostic agent is dissolved or dispersed inan excipient carrier, preferably without any additional material such aspreservatives that might affect the patient. When the contents must bestored in a dry state, the package farther includes another containerthat holds the liquid and can be combined with the dry drug immediatelyprior to administration.

[0051] The term “container” is used herein to mean a receptacle forholding and/or storing a drug formulation. The container can besingle-dose or multidose, and/or disposable or refillable.

[0052] The term “cassette” shall be interpreted to mean a containerwhich holds, in a protective cover, a package or a plurality of packageswhich packages are interconnected to each other and held in the cassettein an organized manner, e.g., interfolding or wound. The cassette isconnectable to a dispensing device, which dispensing device may includea power source, e.g., one or more batteries which provide power to thedispensing device.

[0053] The term “low resistance filter” shall be interpreted to mean afilter of material having any given outer parameter shape, and having aplurality of openings therein, which openings may be placed in a regularor irregular pattern. The openings in the filter can be of any shape,and are preferably substantially evenly distributed throughout thefilter surface area. Preferably, the porosity of the low resistancefilter is greater than 50%, preferably at least 60%, more preferably atleast 70%. Preferably, the low resistance filter prevents passage ofparticles greater than about 0.5 microns in size (e.g., having adiameter greater than 0.5 microns). Where the filter openings are pores,the pores can have a diameter in the range of from about 0.25 micron to6 microns for respiratory tract delivery, or from about 5 microns to 50microns for ocular delivery. The filter has an opening density in therange of from about 10 to 20,000,000 openings per mm². Preferably thefilter has holes of about 0.5 μm positioned about 0.5 μm apart at adensity of 106 holes per mm₂ Preferably, the ratio of the pore densityof the porous membrane to the low resistance filter is in the range ofabout 1:1.5 to about 1:100,000; the ratio of the pore diameter of thepores of the porous membrane to the diameter of the openings of the lowresistance filter is in the range of from about 1:0.95 to 1:0.1.Preferably, the flow resistance of the filter is the same as or lowerthan the flow resistance of the porous membrane used in conjunction withthe filter, The filter is preferably comprised of a material having adensity in the range of 0.25 to 3.0 mg/cm², more preferably 1.7 mg/cm²,and a thickness of about 10 microns to about 500 microns, morepreferably about 20 to 150 microns. The filter can be made of anymaterial suitable for use in the invention, e.g., cellulose ester, mixedcellulose ester, modified polyvinylidene fluoride,polytetrafluoroethylene, bisphen polycarbonate, borosilicate glass,silver, polypropylene, polyester, polyimide, polyether, or any suitablepolymeric material The filter material includes materials such aspolycarbonates and polyesters which may have the pores formed therein byany suitable method, including anisotropic etching or by etching througha thin film of metal or other suitable material, electron dischargemachining, or laser micromachining. The filter preferably has sufficientstructural integrity such that it is maintained intact (i.e., will notrupture) when subjected to force up to about 40 bar, preferably up toabout 50 bar during extrusion of the formulation through the pores (offilter or membrane). The porosity of the low resistance filter is 5-85%,preferably 70%, while the porosity of the nozzle is 10⁻⁴%-1%, preferably0.001%-0.1%

[0054] The term “flow resistance” shall be interpreted to mean theresistance associated with the passage of a liquid or aerosol through aporous material, e.g., through the porous membrane or the low resistancefilter described herein. Flow resistance is affected by the size anddensity of poses in the porous material, the viscosity of a liquidpassing through the material, and other factors well known in the art.In general, “low resistance” of the “low resistance filter” means thatthe flow resistance of the low resistance filter is substantially thesame as or less than the flow resistance of the porous membrane used inconjunction with the low resistance filter.

[0055] The terms “drug”, “active agent”, “pharmaceutically active drug”and the like are used interchangeably herein to encompass compoundswhich are administered to a patient in order to obtain a desiredpharmacological effect. The effect may be a local or topical effect inthe eye or respiratory tract such as in the case of most respiratory orophthalmic drugs or may be systemic as with analgesics, narcotics,hormones, hematopoietic drugs, various types of peptides includinginsulin, and hormones such as erythropoieitin (EPO). Also included arepolynucleotides encoding peptides, polypeptides, antisensepolynucleotides, and ribozymes which have a desired pharmacologicaleffect. Polynucleotides include, but are not limited to, polynucleotidesencoding a DNase, a functional cystic fibrosis transmembrane conductanceregulator (CFTR), and a peptide hormone. Combinations of one or more ofthe foregoing are also encompassed in the term “active agent”. Otherexemplary drugs are set forth in U.S. Pat. Nos. 5,419,315; 5,884,620;5,888,477; 5,724,957; 5,558,085; 5,819,726; International PatentApplication WO 96/13291; and International Patent Application WO96/13290, all incorporated herein by reference to describe and disclosedrugs.

[0056] The term “respiratory drug” shall be interpreted to mean anypharmaceutically effective compound used in the treatment of anyrespiratory disease and in particular the treatment of diseases such asasthma, bronchitis, emphysema and cystic fibrosis. Useful “respiratorydrugs” include those which are listed within the Physician's DeskReference (most recent edition). Such drugs include beta adrenergicagonists which include bronchodilators including albuterol,isoproterenol sulfate, metaproterenol sulfate, terbutaline sulfate,pirbuterol acetate, salmeterol xinotoate, formoteorol; steroidsincluding corticosteroids used as an adjunct to beta agonistbronchodilators such as beclomethasone dipropionate, flunisolide,fluticasone, budesonide and triamcinolone acetonide; antibioticsincluding antifungal and antibacterial agents such as chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fisidic acid, gentamicin,ncomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines, and the like; and also includes peptidenonadrenergic noncholinergic neurotransmitters and anticholinergics.Antiinflammatory drugs used in connection with the treatment ofrespiratory diseases include steroids such as beclomethasonedipropionate, triamcinolone acetonide, flunisolide and fluticasone.Other antiinflammatory drugs and antiasthmatics which includecromoglycates such as cromolyn sodium. Other respiratory drugs whichwould qualify as bronchodilators include anticholinergics includingipratropium bromide. Other useful respiratory drugs include leukotriene(LT) inhibitors, vasoactive intestinal peptide (VIP), tachykininantagonists, bradykinin antagonists, endothelin antagonists, heparinfurosemide, antiadhesion molecules, cytokine modulators, biologicallyactive endonucleases, recombinant human (rh) DNase, α, antitrypsin andantibiotics such as gentamicin, tobramycin, cephalosporins orpenicillins, nucleic acids and gene vectors. The present invention isintended to encompass the free acids, free bases, salts, amines andvarious hydrate forms including semihydrate forms of such respiratorydrugs and is particularly directed towards pharmaceutically acceptableformulations of such drugs which are formulated in combination withpharmaceutically acceptable excipient materials generally known to thoseskilled in the art—preferably without other additives such aspreservatives. Preferred drug formulations do not include additionalcomponents such as preservatives which have a significant effect on theoverall formulation. Thus preferred formulations consist essentially ofpharmaceutically active drug and a pharmaceutically acceptable carrier(e.g., water and/or ethanol). However, if a drug is liquid without anexcipient the formulation may consist essentially of the drug providedthat it has a sufficiently low viscosity that it can be aerosolizedusing a dispenser of the present invention.

[0057] The term “ophthalmic drug” or “ophthalmic treatment fluid” refersto any pharmaceutically active compound used in the treatment of anyocular disease. Therapeutically useful compounds include, but are notlimited to, (1) antiglaucoma compounds and/or compounds that decreaseintraocular pressure such as 62 -adrenoceptor antagonists (e.g.,cetamolol, betaxolol, levobunolol, metipranolol, timolol, etc.),mitotics (e.g., pilocarpine, carbachol, physostigmine, etc.),sympatomimetics (e.g., adrenaline, dipivefrine, etc.), carbonicanhydrase inhibitors (e.g., acetazolamide, dorzolamide, etc.),prostaglandins (e.g., PGF-2 alpha); (2) antimicrobial compoundsincluding antibacterial and antifungal compounds (e.g., chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin,neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines, etc.), (3) antiviral compounds (e.g., acyclovir,cidofovir, idoxuridine, interferons, etc.), (4) aldose reductaseinhibitors (e.g., tolrestat, etc.), (5) antiinflammatory and/orantiallergy compounds (e.g., steroidal compounds such as betamethasone,clobetasone, dexamethasone, fluorometholone, hydrocortisone,prednisolone, etc. and nonsteroidal compounds such as antazoline,bromfenac, diclofenac, indomethacin, lodxamide, saprofen, sodiumcromoglycate, etc., (6) artificial tear/dry eye therapies, comfortdrops, irrigation fluids, etc. (e.g., physiological saline, water, oroils; all optionally containing polymeric compounds such asacetylcysteine, hydroxyethylcellulose, hydroxymellose, hyaluronic acid,polyvinyl alcohol, polyacrylic acid derivatives, etc.), (7) localanaesthetic compounds (e.g., amethocaine, lignocaine, oxbuprocaine,proxymetacaine, etc.), (8) compounds which assist in the healing ofcorneal surface defects (e.g., cyclosporine, diclofenac, urogastrone andgrowth factors such as epidermal growth factor), (9) mydriatics andcycloplegics (e.g., atropine, cyclopentolate, homatropine, hyoscine,tropicamide, etc.), (10) compounds for the treatment of pterygium (e.g.,mitomycin C., collagenase inhibitors such as batimastat, etc.), (11)compounds for the treatment of macular degeneration and/or diabeticretinopathy and/or cataract prevention, (12) compounds for systemiceffects following absorption into the bloodstream after ocularadministration (e.g., insulin, narcotics, analgesics, anesthetics).

[0058] The terms “diagnostic” and “diagnostic agent” and the like areused interchangeably herein to describe any compound that is deliveredto a patient in order to carry out a diagnostic test or assay on thepatient. Such agents are often tagged with a radioactive or fluorescentcomponent or other component which can be readily detected whenadministered to the patient. Exemplary diagnostic agents include, butare not limited to, methacholine, histamine, salt, specific allergens(such as pollen or pollen extracts), sulphites, and imaging agents formagnetic resonance imaging and/or scintigraphy. Diagnostic agents can beused to, for example, assess bronchial constriction in patients havingor suspected of having cystic fibrosis or asthma. Radiolabelled aerosolscan be used to diagnose pulmonary embolism, or to assess mucociliaryclearance in various chronic obstructive diseases of the lung. Otherdiagnostic compounds include sensory compounds, including biocompatiblecompounds with distinctive taste, smell, or color, e.g., to assess theefficacy of aerosol delivery. Diagnostic agents can also be used toassess ophthalmic conditions. Exemplary ocular diagnostic agentsinclude, but are not limited to, such compounds as fluorescein or rosebengal. Diagnostic agents are described and disclosed in U.S. Pat. No.5,792,057.

[0059] The term “formulation” is intended to encompass any drug ordiagnostic agent formulation which is delivered to a patient using thepresent invention. Such formulations generally include the drug ordiagnostic agent present within a pharmaceutically acceptable inertcarrier. The formulation is generally in a liquid flowable form whichcan be readily aerosolized, the particles having a particle size in therange of 0.5 to 12 microns in diameter for respiratory administration.Formulations can be administered to the patient using device of theinvention can be administered by nasal, intrapulmonary, or oculardelivery.

[0060] The terms “aerosol,” “aerosolized formulation,” and the like, areused interchangeably herein to describe a volume of air which hassuspended within it particles of a formulation comprising a drug ordiagnostic agent. The particles preferably have a diameter in the rangeof 0.5 to 12 microns, for respiratory therapy, or in the range of 15 to50 microns for ocular therapy.

[0061] The term “aerosol-free air” is used to describe a volume of airwhich is substantially free of other material and, in particular,substantially free of particles of aerosolized drug.

[0062] The term “dosing event” shall be interpreted to mean theadministration of drug or diagnostic agent to a patient by the ocular orrespiratory (e.g., nasal or intrapulmonary) route of administration(i.e., application of a formulation to the patient's eye or to thepatient's respiratory tract by inhalation of aerosolized particles)which event may encompass one or more releases of drug or diagnosticagent formulation from a dispensing device over a period of time of 15minutes or less, preferably 10 minutes or less, and more preferably 5minutes or less, during which period multiple administrations (e.g.,applications to the eye or inhalations) may be made by the patient andmultiple doses of drug or diagnostic agent may be released andadministered. A dosing event shall involve the administration of drug ordiagnostic formulation to the patient in an amount of about 10 μl toabout 1,000 μl in a single dosing event. Depending on the drugconcentration in the formulation, a single package may not containsufficient drug for therapy or diagnosis. Accordingly, a dosing eventmay include the release of drug or diagnostic agent contained fromseveral containers of a package held in a cassette or the drug ordiagnostic agent contained within a plurality of such containers whenthe containers are administered over a period of time, e.g., within 5 to10 minutes of each other, preferably within 1-2 minutes of each other.

[0063] The term “velocity of the drug” or “velocity of particles” shallmean the average speed of particles of drug or diagnostic agentformulation moving from a release point such as the porous membrane ofthe nozzle or a valve to a patient's mouth or eye. In a preferredembodiment pertaining to respiratory therapy, the relative velocity ofthe particles is zero or substantially zero with reference to the flowcreated by patient inhalation.

[0064] The term “bulk flow rate” shall mean the average velocity atwhich air moves through a channel.

[0065] The term “flow boundary layer” shall mean a set of pointsdefining a layer above the inner surface of a channel through which airflows wherein the air flow rate below the boundary layer issubstantially below the bulk flow rate, e.g., 50% or less than the bulkflow rate.

[0066] The term “carrier” shall mean a flowable, pharmaceuticallyacceptable excipient material, which is not in itself pharmaceuticallyactive. The carrier is preferably a liquid, flowable material, in whicha drug or diagnostic agent is suspended in or more preferably dissolvedin. Useful carriers do not adversely interact with the drug ordiagnostic agent and have properties which allow for the formation ofaerosolized particles, which particles preferably have a diameter in therange of 0.5 to 12.0 microns that are generated by forcing a formulationcomprising the carrier and drug or diagnostic agent through pores havingan unflexed diameter of 0.25 to 6.0 microns for delivery to therespiratory tract. Similarly, a useful carrier for delivery to the eyedoes not adversely interact with the drug or diagnostic agent and hasproperties which allow for the formation of aerosolized particles, whichparticles preferably have a diameter of 15 to 50 microns and aregenerated by forcing the formulation comprising the carrier and drug ordiagnostic agent through pores 7.5 to 25 microns in relaxed diameter.Preferred carriers include water, ethanol, saline solutions and mixturesthereof, with pure water being preferred. Other carriers can be usedprovided that they can be formulated to create a suitable aerosol and donot adversely affect human tissue or the drug or diagnostic agent to bedelivered.

[0067] The term “measuring” describes an event whereby the (1) totallung capacity, (2) inspiratory flow rate or (3) inspiratory volume ofthe patient is measured and/or calculated and the information used inorder to determine an optimal point in the inspiratory cycle at which torelease an aerosolized and/or aerosol-free volume of air. An actualmeasurement of both rate and volume may be made or the rate can bedirectly measured and the volume calculated based on the measured rate.The total lung capacity can be measured or calculated based on thepatient's height, sex and age. It is also preferable to continuemeasuring inspiratory flow during and after any drug delivery and torecord inspiratory flow rate and volume before, during and after therelease of drug. Such reading makes it possible to determine if drug ordiagnostic agent was properly delivered to the patient.

[0068] The term “monitoring” shall mean measuring lung functions such asinspiratory flow, inspiratory flow rate, and/or inspiratory volume sothat a patient's lung function as defined herein, can be evaluatedbefore and/or after drug delivery thereby making it possible to evaluatethe effect of drug delivery on, for example, the patient's lungfunction.

[0069] The term “inspiratory flow profile” shall be interpreted to meandata calculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is optimal for the release of drugto be delivered to a patient. An optimal point within the inspiratorycycle for the release of an aerosol volume is based, in part, on (1) apoint most likely to deliver the aerosol volume to a particular area ofa patient's respiratory tract, in part on (2) a point within theinspiratory cycle likely to result in the maximum delivery of drug and,in part, on (3) a point in the cycle most likely to result in thedelivery of a reproducible amount of drug to the patient at each releaseof drug. The criteria 1-3 are listed in a preferred order of importance.However, the order of importance can change based on circumstances. Thearea of the respiratory tract being treated is determined by adjustingthe volume of aerosol-containing or aerosol-free air and/or by adjustingthe particle size of the aerosol. The repeatability is determined byreleasing at the same point in the respiratory cycle each time drug isreleased. To provide for greater efficiency in delivery, the drugdelivery point is selected within given parameters.

[0070] The terms “formulation” and “flowable formulation” and the likeare used interchangeably herein to describe any pharmaceutically activedrug (e.g., a respiratory drug, or drug that acts locally orsystemically, and that is suitable for respiratory delivery) ordiagnostic agent combined with a pharmaceutically acceptable carrier inflowable form having properties such that it can be aerosolized toparticles having a diameter of 0.5 to 12.0 microns for respiratorytherapy, or 15 to 75 microns for ocular therapy. Flowable formulationsinclude powders and liquids. Flowable formulations are preferablysolutions, e.g., aqueous solutions, ethanolic solutions,aqueous/ethanolic solutions, saline solutions, colloidal suspensions andmicrocrystalline suspensions. Preferred formulations are drug(s) and/ordiagnostic agent(s) dissolved in a liquid, preferably in water.

[0071] The term “substantially dry” shall mean that particles offormulation include an amount of carrier (e.g., water or ethanol) whichis equal to (in weight) or less than the amount of drug or diagnosticagent in the particle, more preferably it means free water is notpresent.

[0072] The terms “aerosolized particles” and “aerosolized particles offormulation” shall mean particles of formulation comprised of carrierand drug and/or diagnostic agent that are formed upon forcing theformulation through a nozzle, which nozzle comprises a flexible porousmembrane. Where respiratory therapy is desired, the particles are of asufficiently small size such that when the particles are formed, theyremain suspended in the air for a sufficient amount of time forinhalation by the patient through his nose or mouth. Where oculartherapy is desired, the particles formed are of a size optimal forapplication to the eye. Preferably, particles for respiratory deliveryhave a diameter of from about 0.5 micron to about 12 microns, and aregenerated by forcing the formulation through the pores of a flexibleporous membrane, where the pores have an unflexed exit aperture diameterin the range of about 0.25. micron to about 6.0 microns. Morepreferably, the particles for respiratory delivery have a diameter ofabout 1.0 to 8.0 microns with the particles created by being movedthrough pores having an unflexed exit aperture diameter of about 0.5 toabout 4 microns. For ocular delivery, the particles have a diameter fromabout 15 micron to about 75 microns, and are generated by forcing theformulation through the pores of a flexible porous membrane, where thepores have an unflexed exit aperture diameter in the range of about 5micron to about 50 microns. More preferably, the particles for oculardelivery have a diameter of about 15 to 50 microns, and can be generatedby forcing the formulation through flexible membrane pores having anunflexed exit aperture diameter of about 7.5 to about 25 microns. Ineither respiratory or ocular delivery, the flexible membrane pores arepresent at about 10 to 10,000 pores over an area in size of from about 1sq. millimeter to about 1 sq. centimeter, preferably from about 1×10 ₁to about 1×10₄ pores per square millimeter, more preferably from about1×10₂ to about 3×10₄ pores per square millimeter, and the low resistancefilter has an opening density in the range of 20 to 1,000,000 pores overan area of about one square millimeter.

[0073] The term “substantially through” with reference to the poresbeing formed in the membrane or material shall mean pores which eithercompletely traverse the thickness of the membrane or are formed to havea thin peelable layer over their exit aperture. The pores formed with apeelable layer over their exit apertures are formed so as to peeloutward at a substantially lower pressure than would be required torupture the membrane in the nonporous areas.

[0074] An “individual”, “subject”, or “patient”, used interchangeablyherein, is a mammal, preferably a human.

[0075] Aerosolization Nozzles Comprising Specialized Pore Structures

[0076] The present invention provides thin sheets of membrane comprisingspecialized pore structures. These membranes are useful asaerosolization nozzles. The nozzles of the invention comprise membraneshaving a plurality of pores through which a flowable formulation isaerosolized for delivery to a subject. The plurality of pores passesthrough a “nozzle area” of the membrane, i.e., the area of the membranethrough which the formulation is extruded and aerosolized. The materialused may be any material from which suitable pores can be formed andwhich does not adversely interact with other components of the deliverydevice, particularly with the formulation being administered.

[0077] Pore Characteristics and Configurations

[0078] A critical feature of the membranes comprising specialized porestructures of the invention is the entrance aperture diameter to exitaperture diameter ratio of the pore, which in turn relates to thepressure needed to generate an aerosol. The ratio of the entranceaperture diameter to exit aperture diameter of these pores issignificantly higher than that previously achieved. Accordingly, thepresent invention provides nozzles having pores with entrance aperturediameter to exit diameter ratio of at least about 10:1, more preferablyat least about 12.5:1, more preferably at least about 15:1, morepreferably at least about 20:1, more preferably at least about 25:1, upto about 100:1.

[0079] The pores can be of any shape, including, but not limited to,multi-step and tapered. Tapered pores are generally conical, where“conical” means that the pores are larger on one side of the membranethan on the other side, and that the diameter decreases in a continuous,linear fashion, i.e., a smooth curve, and includes instances where thecross-section of the pores is conical or curved. Multi-step pores canhave two, three, four, or more steps, as necessary to achieve areduction in the pressure needed to generate an aerosol. The number ofsteps is not critical to the aerosolization nozzles of the presentinvention. The height and aperture size of each pore step may dependupon the thickness of the membrane material. In some embodiments, thepore step adjacent to the entrance side of the membrane has a height offrom about 20% to about 90%, usually from about 40% to about 80%, of thethickness of the material. Each pore step may be roughly cylindrical orconical in shape, where “cylindrical” means that the steps passperpendicularly through the membrane and have approximately the samediameter throughout their length, and “conical” means that the pores arelarger on one side of the membrane than on the other side, and that thediameter decreases in a continuous, linear fashion, and includesinstances where the cross-section of the pores is conical or curved. Insome embodiments, the through-steps are conical.

[0080] When the pores, pore steps, or through-steps of the pores areconical, the wider diameter of the cone is found on the entrance side ofthe pore to which the formulation is applied under pressure, while thesmaller diameter of the cone is closer to the exit side of the pore fromwhich aerosolization occurs. The exit aperture size of the pores ispreferably uniform; following the methods taught herein, the variabilityin exit aperture size is generally less than about 10%, usually lessthan about 5%. The nozzle may be provided as an integral part of theformulation packaging, or may be provided separately, for exampleintegrally with the inhalation device, or wound on a roll for disposableuse.

[0081] The pore structures described herein are formed in a membrane foruse in an aerosolization device, and allow generation of aerosols atsignificantly lower aerosolization pressures than was previouslyachievable. Accordingly, the pore structures of the present invention,when formed in membranes used in an aerosolization device, allowaerosolization of a flowable formulation at extrusion pressures lessthan about 500 psi, generally in a range of about 100 psi to about 500psi, usually in a range of about 200 psi to about 400 psi. In general,the amount of pressure required is greater than about 100 psi, and lessthan about 500 psi.

[0082] For respiratory delivery, the pores are formed so as to have anunflexed exit aperture diameter from about 0.25 to 6.0 microns in size,preferably 0.5 to 5.0 microns. When the pores have this size, thedroplets that are formed will have a diameter about twice the diameterof the pore size. In some cases, it may be desirable to generateaerosols having an aerodynamic size in a particular range. Thus, it maybe of interest to generate particles having an aerodynamic size in therange of 1-3 μm, 4-6 μm, or 7-10 μm. Exit pore aperture sizes would beadjusted accordingly.

[0083] The terms “particle diameter”, “particle size” and the like areused interchangeably herein to refer to particle size as given in the“aerodynamic” size of the particle. The aerodynamic diameter is ameasurement of a particle of unit density that has the same terminalsedimentation velocity in air under normal atmospheric conditions as theparticle in question. When small (e.g., 1-50 micrometer diameter)particles are said to have the same diameter, they have the sameterminal sedimentation velocity. This is pointed out in that it isdifficult to accurately measure the diameter of small particles usingcurrent technology and the shape of such small particles may becontinually changing. For ocular delivery, the pores are formed so as tohave an unflexed exit aperture diameter in the range of 5 microns to 50microns, preferably 7.5 to 25 microns.

[0084] The pores can be spaced from about 10 to about 1000 μm apart ormore, but are preferably spaced from about 30 to about 70 μm apart, mostpreferably about 50 μm apart. The pore spacing is determined in part bythe need to prevent the aerosol from adjacent pores from adverselyinterfering with each other, and in part to minimize the amount ofmembrane used and the associated manufacturing difficulties and costs.The pore spacing is preferably fairly uniform, with a variability in theinterpore distance of preferably less than about 20%, more preferablyless than about 1O%, and most preferably about 2% or less (<1 μmvariability for pores spaced 50 μm apart).

[0085] The pores in a nozzle area may be arranged in regular arrays,such as in rows or grids of pores at regular, substantially uniformdistances from one another. In one embodiment of the invention, thepores are formed in a 7×48 array of pores spaced 50 μm apart.

[0086] A given membrane may have a plurality of nozzle areas, at a givendistance from an adjacent nozzle area, and separated from adjacentnozzle area by a section of non-porous membrane. In some embodiments,the membrane is a strip comprising a plurality of nozzle areas separatedfrom one another by non-porous membrane areas.

[0087] The amount of liquid being aerosolized is generally from about 10μl to about 100 milliliters. In some embodiments, the amount of liquidis in a range of from about 5 milliliters (ml) to about 100 milliliters,from about 10 milliliters to about 90 milliliters, from about 20milliliters to about 80 milliliters, from about 40 milliliters to about60 milliliters. In other embodiments, the amount of liquid is in a rangeof from about 0.5 ml to about 10 ml, from about 1 ml to about 8 ml, fromabout 2 ml to about 6 ml. In still other embodiments, the amount ofliquid is in a range of from about 10 μl to about 1000 μl, from about 20μto about 100 μl.

[0088] The density of pores in the nozzle area ranges from 1 to about1,000 pores, generally about 100 to about 900 pores, per squaremillimeter. In some embodiments, the pore density in the nozzle area isabout 100 pores per square millimeter. In other embodiments, thisdensity is about 200 pores per square millimeter.

[0089] The period of time over which the formulation is to beadministered must also be considered. The delivery time is a criticalparameter, as it is necessary to generate the aerosol during asufficiently short period of time so that the aerosol may be targeted toa specific area of the respiratory tract during inspiration. For a givenpore exit diameter and formulation pressure, hole number can be adjustedto control delivery time. Generally, aerosolization will occur withinabout 0.5 to about 5 seconds, usually in a range of about 1 second toabout 2 seconds.

[0090] In one embodiment, the pores are incompletely formed so that athin peelable layer remains covering the exit apertures of the pores.This peelable layer bursts outward upon forcible application of the drugformulation to the nozzle during drug delivery, permittingaerosolization of the formulation. The peelable layer of the pores isformed so as to have a breaking pressure significantly below that of theoverall membrane, and the pressure at which the layer bursts issignificantly below that applied in the normal course of drugadministration, so that the pores burst substantially uniformly andcompletely. The incompletely formed pores may be formed by applicationof a thin layer of material to the outer side of the membrane afterformation of complete pores, or by incompletely ablating holes throughthe membrane.

[0091] In another embodiment, the pores are provided with elevated areassurrounding the exit aperture, so as to prevent liquid from intrudingfrom the outer surface of the membrane back into the pore and therebydisrupting aerosolization. The elevated areas may be of any shape, suchas circular or rectangular, or may be irregularly shaped. The elevatedareas can be constructed by any suitable means, for example by etchingaway portions of the outer layer of the membrane, by laser drillingprocedures which lead to sputtering of material around the pores, bymolding or casting, by deposition of material via a mask in locationswhere pores are to be formed, and the like.

[0092] A pore may be formed so as to have an elevated area via excimerlaser ablation from the opposite side of the membrane. The formation ofthe elevated area via excimer laser ablation can be controlled byaltering the pulse number: a minimal number of pulses used to penetratethe membrane will form an elevated area around the aperture on theopposite side of the membrane; increasing the number of pulses will thenremove this elevated area. For example, for a 25 micron thick polyimidemembrane, 120 pulses of a 308 nm excimer laser at an energy density of630 mJ/cm² will form a pore having an elevated area, while increasingthe number of pulses above 150 will remove the elevated area andslightly widen the pore aperture. The elevated areas may be of anysuitable dimensions, but preferably extend significantly less than theinterpore distance so as to provide lower areas where fluid issequestered. The elevated areas can be made from any suitable material,for example the material comprising the bulk of the membrane, or may bemade from materials with desirable properties such as hydrophobicity orsolvent or drug repellence so as to repel the drug formulation fromentering the exit aperture of the pores,

[0093] Membrane Materials and Characteristics

[0094] The membrane material is preferably hydrophobic and includes, butis not limited to, materials such as polycarbonates, polyimides,polyamides, polysulfone, polyolefin, polyurethane, polyethers, polyetherimides, polyethylene and polyesters which may have the pores formedtherein by any suitable method including, but not limited to, laserdrilling, electron discharge machining, or anisotropic etching through athin film of metal or other suitable material. Co-polymers of theforegoing can also be used. Shape memory polymers, which are known inthe art and have been described in, inter alia, U.S. Pat. No. 5,910,357,can also be used. Preferably, the membrane is one that does not interactchemically with the substance being aerosolized, or the aerosolizationsolvent. The membrane preferably has sufficient structural integrity sothat it is maintained intact (will not rupture) when subjected to forcein the amount up to about 580 psi, preferably of up to about 725 psi,while the formulation is forced through the pores.

[0095] In some embodiments, the material is a flexible polymeric organicmaterial, for example a polyether, polycarbonate, polyimide, polyetherimide, polyethylene or polyester. Flexibility of the material ispreferred so that the nozzle can adopt a convex shape and protrude intothe airstream upon application of pressure, thus forming the aerosolaway from the static boundary layer of air. Material which issubstantially non-flexible can also be used, and, if such material isused, is preferably shaped to have a convex configuration.

[0096] As would be apparent to those skilled in the art who read thisdisclosure, the nozzle area is the porous membrane area. That area maybe integral with surrounding sheet material (i.e. a porous area of sheetor tape) or be a separate membrane covering an opening in a thin sheetor tape (i.e., a porous membrane sheet separate from the surroundingsheet or tape). In some embodiments, the porous membrane is covered by aremovable cover sheet detachably connected to the porous membrane.

[0097] The thickness of the membrane affects both the manufacturing ofthe nozzles and containers as well as the pressure required to generatethe desired aerosol during administration. Thinner membranes requireless pressure to generate an aerosol, but are conversely more difficultto handle during manufacturing, for example in laminating the membraneto other components of the formulation container. The membrane ispreferably about 10 to about 100 μm in thickness, from about 15 to about40 micrometers, from about 20 to about 30 micrometers, more preferablyfrom about 12 to about 45 μm in thickness. In one embodiment, themembrane material is a 25 μm thick film of polyimide. Considerations forthe membrane material include the ease of manufacture in combinationwith the formulation container, flexibility of the membrane, and thepressure required to generate an aerosol from pores spanning a membraneof a given material, thickness and flexibility.

[0098] Methods For Generating Pores In Reduced Pressure ExtrusionNozzles

[0099] The present invention provides methods for generating specializedpore structures as described above in thin sheets of material. Suitablemethods include, but are not limited to, laser ablation(micromachining), anisotropic etching, and electron discharge machining.Pores can be formed by a single-step or a multi-step method. Thesemethods include, but are not limited to, a multi-step process; aone-step process using a single, variable-density mask; and dithering.These methods are described below. Membranes comprising thesespecialized pore structures are useful in aerosolization nozzles.Accordingly, the invention provides methods of making aerosolizationnozzles. These nozzles can be used in reduced-pressure aerosolizationdevices

[0100] In some embodiments, laser ablation is used to form tapered ormulti-step pores as described herein in the membrane. The particularlaser source used in the method of the invention will to some extent bedetermined by the material in which the pores are to be formed.Generally, the laser source must supply a sufficient amount of energy ofa wavelength which can form an effective aerosolization nozzle in thematerial being ablated. Typically, for an organic polymer membrane, thewavelength is from about 150 nm to about 360 nm.

[0101] The output of the particular laser source can be manipulated in avariety of ways prior to being applied to the material. For example, thefrequency can doubled or tripled using, for example, a lithium triboratecrystal or series of crystals, or a combination thereof. This laser beamcan be further split into multiple beams to create multiple poressimultaneously. The beam can also be directed through a mask orspatially filtered, and can also be expanded prior to focusing.

[0102] One laser effective for such nozzles is a neodymium-yttriumaluminum garnet laser. This laser can be configured to provide a pulsedultraviolet wavelength light source which provides sufficiently highpeak power in short pulses to permit precise ablation in a thinmaterial. The beam profile from this laser is radially symmetric whichtends to produce radially symmetric pores.

[0103] Another laser effective for creating pores in materials such aspolyethers and polyimides is an excimer laser. This laser also producesultraviolet wavelength light. However, the beam is not radiallysymmetrical but is projected through a mask to simultaneously drill oneor more conical or cylindrical holes. In some embodiments, the lasersource is an excimer laser providing a wavelength of 308 nm. The energydensity used for such a laser typically ranges from about 300 to about800 mJ/cm², from about 400 mJ/cm² to about 700 mJ/cm², from about 500mJ/cm² to about 700 mJ/cm². In some embodiments, the energy density isabout 630 mJ/cm². Using such a laser on a 25 μm thick polyimidemembrane, the number of pulses is typically about 40 to about 200. Thoseskilled in the art will readily appreciate that these parameters can bevaried, depending on the thickness of the membrane being drilled.

[0104] The methods of the present invention for producing a porousmembrane, generally comprise the steps of: directing laser energy ontoan entrance surface of a membrane and continuing to direct the energyuntil the laser has created a pore having an entrance aperture and anexit aperture having a pore entrance aperture size and a pore exitaperture size, wherein the ratio of pore entrance aperture size to poreexit aperture size is at least about 10:1. The directing of laser energycan be repeated a plurality of times, by repositioning the laser energyfor each directing step, or by repositioning the membrane for eachdirecting step.

[0105] Multi-Step Methods

[0106] A pore as described herein can be made by multi-step methods. Thepores are ablated in stepwise fashion from the entrance side of themembrane to form steps of decreasing diameter toward the exit side ofthe membrane. This decreases the total number of laser pulses necessaryto generate a pore having a wider entrance aperture and a narrower exitaperture, and allows for entrance aperture diameters which could not beachieved via single-step methods for a given exit aperture diameter.

[0107] The multistep methods generally comprise the steps of: directinglaser energy onto a first surface of a membrane having a thickness X andcontinuing to direct the energy until the laser has created an entrancehole into the first surface having a depth of X/Y wherein Y is greaterthan X and less than 10X and the entrance hole has a diameter D;directing laser energy onto a second surface at the bottom of the holeuntil the laser has created an exit hole having a diameter D/d wherein dis greater than D and is less than 10D wherein the depth of the entrancehole combined with the depth of the exit hole is a depth in a range offrom X to 0.95X. In general, Y is in a range of about 4X to about 0.5X,usually in a range of about 2X to about 1.0X. Typically Y is about2X±10%.

[0108] To form a multi-step pore, a first pore step is formed to a depthh1(resulting in a first pore step height h1) in a membrane, startingfrom the entrance side of the membrane, wherein h1 is less than thethickness of the membrane, and is generally about 20% to about 90%,generally about 40% to about 80% of the thickness of the membrane. Thefirst pore step has an entrance aperture size and an exit aperture size.A second pore step is then formed to a depth h2 (resulting in a secondpore step height h2), which in turn has an entrance aperture size and anexit aperture size. The second pore step entrance aperture size isgenerally about 20% to about 90%, generally about 40% to about 80% ofthe first pore step aperture size. The second pore step exit aperturecan also be the pore exit, or can lead to a third pore step. In general,the entrance aperture size of a given pore step is about 20% to about90%, generally about 40% to about 80%, of the exit aperture size of thepreceding, membrane entrance side-proximal, pore step. This process isshown schematically in FIG. 2.

[0109] For example, a two-step pore can be formed by directing about40-60 pulses of an excimer laser beam at a fluence level of 625 mJ/cm²so as to form a 25 μm entrance aperture diameter first pore step to adepth of 10-20 μm through a 25 μm thick polyimide film, resulting in afirst pore step having a height of 10-20 μm. A second beam of similarfluence can then be directed coaxially, or nearly coaxially, for about50-75 pulses into the partially ablated first pore step so as to have a4-6 μm entrance aperture diameter from the bottom of the partiallyablated first pore step through to the exit side of the membrane toproduce a pore having an exit aperture of about 1.0 to about 1.5 μm,e.g. 1.2 μm, thereby forming a second pore step having a 4-6 μm entranceaperture diameter and a 1.0 to about 1.5 μm exit diameter. The resultingmulti-step pore has an entrance aperture diameter to exit aperturediameter ratio of about 20:1 to about 25:1.

[0110] Each step which does not pass through to the exit side of themembrane can have one or more further steps or through-steps ablatedfrom its exit side terminus. Up to the entire nozzle area of themembrane can be ablated in forming the first step or series of steps.The entire array of through-steps can then be ablated in this ablatedarea. The result is that, for a two-step process, the entire nozzle areaof a 25 μm thick polyimide film can be ablated in the first step to adepth of 10-20 μm, and the entire array of through-steps can then beablated through the remainder of the membrane.

[0111] Single-Step Methods

[0112] Any of a number of single-step methods are available for use ingenerating pore structures for reduced-pressure aerosolization.

[0113] One such method makes use of a single mask having avariable-density dot pattern, as described in U.S. Pat. No. 5,417,897,which method is specific to making a hole for an ink jet printer nozzle.Using this method, a mask may comprise an open central region, whichallows 100% transmission of the laser energy. Surrounding and continuouswith the open central region is a second region in which the maskmaterial is arranged in a pattern of opaque dots which act to partiallyshield a membrane in which pores are to be formed. By selecting adensity of opaque dots in the peripheral region around the centralopening, the central portion of each nozzle formed will be completelyablated through, and the peripheral portions of the nozzle will be onlypartially ablated. Transmission of laser energy in the first peripheralregion is about 20 to about 65%. A second peripheral region can be madesuch that the transmission is less than in the first peripheral region.By varying the density of the opaque dots in the first and (optional)second peripheral regions, the pore formed in the nozzle membrane can bemade to a desired shape. This process is sometimes referred to herein asa “Grayscale process”.

[0114] Another method for making pores having the characteristicsdescribed above involves use of dithering, or rotating an optical mirrorto rotate a laser beam during the ablation process. By changing therotation of the mirror, the laser beam can be focused onto an area ofsuccessively decreasing size through the thickness of the membrane,thereby forming a reduced-pressure aerosolization pore having thecharacteristics described herein. The dithering method has been amplydescribed in the literature, including, for example, in U.S. Pat. No.4,894,115.

[0115] Nozzle And Container Configurations

[0116] The present invention provides containers for aerosolizing aflowable formulation, the containers comprising the nozzles comprisingspecialized pore structures, as described above. Further provided aremethods of making the containers.

[0117] In general, the nozzle comprised of a porous membrane accordingto the invention can be used in conjunction with any container suitablefor containing a drug or diagnostic agent formulation of interest. Thecontainer can be, for example, a single-dose container or a multidosecontainer. Examples of single-dose and multi-dose containers areprovided in Example 2 and in FIGS. 6 and 7. The containers can berefillable, reusable, and/or disposable. Preferably, the container isdisposable. The container can be designed for storage and delivery of adrug or diagnostic agent that is dry, substantially dry, liquid, or inthe form of a suspension, The container may be any desired size. In mostcases the size of the container is not directly related to the amount ofdrug or diagnostic agent being delivered in that most formulationsinclude relatively large amounts of excipient material, e.g., water or asaline solution. Accordingly, a given size container could include awide range of different doses by varying drug (or diagnostic agent)concentration.

[0118] The present invention provides a container for aerosolizing aflowable liquid formulation for delivery to a patient, comprising: (a) asheet of flexible membrane material having an entrance side to which theformulation is applied under a pressure, an exit side from which aerosolis released, and a nozzle area, which nozzle area has a plurality ofpores therein through which the formulation is extruded, each of thepores having an exit aperture and an entrance aperture having a poreentrance aperture size and a pore exit aperture size, wherein the ratioof pore entrance aperture size to pore exit aperture size is at leastabout 10:1; (b) container walls connected to the sheet wherein a wall ofthe container is collapsible by the application of a force; and (c) aliquid formulation held within the container walls.

[0119] The present invention further provides methods for making theaerosolization containers as described herein, generally comprisingpositioning a sheet of flexible membrane material, which comprisesnozzle areas having pore structures as provided in the presentinvention, adjacent to a container comprising a formulation, such thatthe nozzle is connected to the container, wherein the containercomprises at least one wall collapsible by the application of a force.

[0120] Because the container comprises a nozzle as described above, aforce of about 500 pounds per square inch (psi) or less collapses thecontainer and forces the formulation out of pores of the membrane andaerosolizes the formulation. Generally, the amount of pressure requiredto collapse the container, force the formulation out of the pores of themembrane, and aerosolize the formulation is in a range of about 100 psito about 500 psi, usually in a range of about 200 psi to about 400 psi.In general, the amount of pressure required is greater than about 100psi, and less than about 500 psi.

[0121] Generally, the amount of liquid formulation in the container isgenerally from about 10 μm to about 100 milliliters. In someembodiments, the amount of liquid is in a range of from about 5milliliters (ml) to about 100 milliliters, from about 10 milliliters toabout 90 milliliters, from about 20 milliliters to about 80 milliliters,from about 40 milliliters to about 60 milliliters. In other embodiments,the amount of liquid is in a range of from about 0.5 ml to about 10 ml,from about 1 ml to about 8 ml, from about 2 ml to about 6 ml. In stillother embodiments, the amount of liquid is in a range of from about 10μl to about 1000 μl, from about 20 μm to about 100 μl.

[0122] The time required to aerosolize the formulation is generally inthe range of 0.5 second to 5 seconds, generally about 1 second to about2 seconds.

[0123] The present invention further provides a disposable containercomprising: (a) at least one wall which is collapsible by theapplication of a force and having at least one opening, wherein theopening leads to an open channel having an end; (b) a nozzle asdescribed herein positioned at the end of the open channel, the nozzlecomprising: a sheet of flexible membrane material having an entranceside to which said formulation is applied under a pressure, an exit sidefrom which aerosol is released, and a nozzle area, which nozzle area hasa plurality of pores therein through which the formulation is extruded,each of the pores having an exit aperture and an entrance aperturehaving a pore entrance aperture size and a pore exit aperture size,wherein the ratio of pore entrance aperture size to pore exit aperturesize is at least about 10:1; and (c) formulation in an amount of 100milliliters or less in the container. In some embodiments, the openchannel comprises a seal which is peeled open upon application of aforce exerted upon the collapsible wall. In other embodiments, thedisposable container further comprises a low resistance filterpositioned between the seal and the nozzle. The invention furtherprovides a disposable package comprising one or a plurality of acontainer-of the invention.

[0124] The container can also be one that provides for storage of a drugor diagnostic agent in a dry or substantially dry form until the time ofadministration, at which point, if desired, the drug or diagnostic agentcan be mixed with water or other liquid. An exemplary dual compartmentcontainer for carrying out such mixing of dry drug with liquid justprior to administration is described in U.S. Pat. No. 5,709,202,incorporated herein by reference with respect to such containers.

[0125] In a preferred embodiment, the containers useful with theinvention comprise a single-use, single-dose, disposable container thatholds a formulation for delivery to a patient and has a collapsiblewall. In addition, the container can be configured in the same packagewith a porous membrane and a low resistance filter, where the lowresistance filter is positioned between the porous membrane and aformulation contained in the container. The container is preferablydisposable after a single use in the delivery of the formulationcontained therein.

[0126] In one embodiment, the container is shaped by a collapsible wall.The container has an opening covered by a nozzle comprised of a flexibleporous membrane. The exit apertures of the pores of the nozzle aresurrounded by elevated areas which prevent intrusion of fluid back intothe pores. The container includes an opening which leads to an openchannel which channel includes an abutment (or peelable seal) which ispeeled open upon the application of force created by formulation beingforced from the container. A low resistance filter can be positionedbetween the formulation and the peelable seal. The filter has a porositysuch that the presence of the filter does not substantially increase thepressure required to generate an aerosol by forcing the formulationthrough the porous membrane of the nozzle. When the abutment is peeledopen, the formulation flows to an area adjacent to the nozzle's flexibleporous membrane and is prevented from flowing further in the channel bya nonbreakable abutment.

[0127]FIG. 6 is a cross-sectional view of a preferred embodiment of adisposable container 1 of the invention. The container is shaped by acollapsible wall 2. The container 1 includes an opening which leads toan open channel 6, which channel 6 includes an abutment (or peelableseal) 7 which is peeled open upon the application of force created byformulation 5 being forced from the container. A low resistance filter301 is positioned between the peelable seal 7 and the nozzle 302. Whenthe peelable seal 7 is broken, the formulation 5 flows to an areaadjacent the low resistance filter 301, through the low resistancefilter 301, if present, and out the nozzle 302 to form an aerosol. Theformulation 5 is prevented from flowing further in the channel 6 by anonbreakable abutment 8. A number of containers can be connectedtogether to form a package 46 as shown in FIG. 7. The package 46 isshown in the form of an elongated tape, but can be in any configuration(e.g., circular, square, rectangular, etc.). Furthermore, the package 46is shown comprising a single row of containers, but can comprise two ormore rows.

[0128]FIG. 9 is a cross-sectional view of the disposable container 1 ofFIG. 6 in use for respiratory therapy. The wall 2 is being compressed bya mechanical component such as the cam 9, as shown in FIG. 9. The cammay be driven by a motor connected to gears which turn the cam 9 tobring the cam into contact with and apply the necessary force to thecollapsible wall 2 of the container 1. The formulation 5 is forcedthrough the low resistance filter 301, if present, into the open channel6 (breaking the seal 7 shown in FIG. 8), and against and through thenozzle 302 causing the porous membrane of the nozzle 302 to protrudeoutward into a convex configuration as shown in FIG. 7. The cam 9 hasbeen forced against the container wall 2 after a patient 10 beginsinhalation in the direction of the arrow “I.”

[0129] An exemplary method for using the aerosol delivery device 40, asshow follows. The patient 10 inhales through the mouth from a tubularchannel 11. The velocity of the air moving through the flow path 29 ofthe channel 11 can be measured across the diameter of the channel todetermine a flow profile 12, i.e., the air flowing through the channel11 has a higher velocity further away from the inner surface of thechannel. The air velocity immediately adjacent to the inner surface ofthe channel 11 (i.e., infinitely close to the surface) is very slow(i.e., approaches zero). A flow boundary layer 13 defines a set ofpoints below which (in a direction from the channel center toward theinner surface of the channel) the flow of air is substantially below thebulk flow rate, i.e., 50% or less than the bulk flow rate.

[0130] As shown in FIG. 9, the convex shape that the flexible porousmembrane of the nozzle 302 takes on during use plays an important role.Preferably, the upper surface of the flexible porous membrane of thenozzle 302 is substantially flush with (i.e., in substantially the sameplane as) the inner surface of the channel 11 to allow air to flowfreely. Thus, if the membrane of the nozzle 302 remained in place whenthe formulation 5 moved through the pores, the formulation would bereleased into the slow moving or substantially “dead air” below theboundary layer 13. However, when the formulation 5 is forced from thecontainer 1 by force applied from a source such as a motor-driven cam22, the formulation 5 presses against the flexible porous membrane ofthe nozzle 302 causing the porous membrane to convex outward beyond theplane of the resting surface of the nozzle's membrane 302 and beyond theplane of the inner surface of the channel 11. The convex upwarddistortion of the membrane of the nozzle 302 is important because itpositions the pores of the membrane beyond the boundary layer 13 (shownin FIG. 9) into faster moving air of the channel 11.

[0131] A device similar to the device 40 of FIG. 9 can be similarly usedto deliver a drug to the respiratory tract by nasal delivery. Forexample, the mouthpiece 30 and opening 38 are suitably modified toprovide for delivery by nasal inhalation. Thus, the patient places theopening of the modified device into his nostril and, after inhalation, adose of the drug is delivered to the respiratory tract of the patient ina manner similar to that described above.

[0132] Aerosol delivery of a drug to the eye can be accomplished using adevice similar to the device 40 described above, with modifications. Forexample, the device 40 shown in FIG. 9 is modified such that themouthpiece 30, opening 38, and channel are suitable for aerosol deliveryto the surface of the patient's eye. The patient positions the device sothat aerosol formulation exiting the opening 38 will contact the eye'ssurface; the channel is open at the opening end (opening 38) and ispreferably closed at the end opposite the opening end. The device mayadditionally comprise a means to maintain the device in a stableposition over the patient's eye and/or a means for detecting when thepatient's eye is open. Upon activation of the device, a cam 9 (or othermechanical component) crushes the collapsible wall 2 of the container 1.The formulation 5 is forced through the filter 301, into the openchannel 6 (breaking the seal 7), and against and through the nozzle 302,thereby generating an aerosol which is forced out of the device throughan opening so as to come into contact with the surface of the eye.

[0133] The device of the invention can use a low resistance filter and aporous membrane to prevent clogging of the nozzle's porous membrane andto prevent the passage of undissolved particles or drug and/or otherundesirable particles from being delivered to the patient. In general,the formulation is released from a container, passed through at leastone low resistance filter, and then passed through a porous membrane ofa nozzle. An aerosol is formed from the drug formulation when it exitsthe pores of the porous membrane, and the aerosol is delivered to thepatient.

[0134] The nozzle can be included as components of a disposable packagethat is composed of a container that serves as a storage receptacle forthe drug formulation, a porous membrane, and, optionally, a lowresistance filter positioned between the drug formulation and thenozzle. Such filters are described and disclosed in U.S. Pat. No.5,829,435 issued Nov. 3, 1998.

[0135] The nozzle can also be provided separate from the drug containerand/or the disposable package. For example, the nozzle can be providedas a single disposable unit that can be inserted in the proper positionrelative to the container. The disposable nozzle can be inserted priorto use and can be disposed after each use or after a recommended numberof uses. Alternatively, the nozzle can be provided as a separate ribbonor ribbons.

[0136] The formulation may be a low viscosity liquid formulation. Theviscosity of the drug or diagnostic agent by itself or in combinationwith a carrier is not of particular importance except to note that theformulation must have characteristics such that the formulation can beforced out of openings to form an aerosol, e.g., when the formulation isforced through the flexible porous membrane it will form an aerosolpreferably having a particle size in the range of about 0.1 to 1-2microns for intrapulmonary delivery or in the range of 15 to 75 micronsfor ocular delivery.

[0137] Aerosol Delivery Devices

[0138] The present invention further provides aerosol delivery deviceswhich comprise a container as described herein. In general, aerosoldelivery devices useful with the invention comprise (a) a device forholding a formulation-containing container, preferably a disposablecontainer, with at least one but preferably a number of containers, and(b) a mechanical mechanism for forcing the contents of a container (onthe package) through a nozzle comprised of a porous membrane and havingpore structures as provided by the present invention, optionallypreceded by a low resistance filter. Where the device is used forrespiratory delivery, the device can further comprise (c) a means forcontrolling the inspiratory flow profile, (d) a means for controllingthe volume in which the drug or diagnostic agent is inhaled, (e) aswitch for automatically releasing or firing the mechanical means torelease a determined volume of aerosol and aerosol-free air when theinspiratory flow rate and/or volume reaches a predetermined point, (f) ameans for holding and moving one package after another into a drugrelease position so that a new package is positioned in place for eachrelease of drug, and (g) a source of power, e.g., spring, orconventional batteries or other source of electric power.

[0139] The present invention further provides methods for making aerosoldelivery devices as described herein, generally comprising disposing acontainer as described herein in a holding device, wherein the holdingdevice is coupled to a mechanical mechanism for forcing the contents ofthe container through the nozzle of the container.

[0140]FIG. 10 is a cross-sectional view of an aerosol delivery device ofthe invention having a multidose container and a ribbon of lowresistance filters and a ribbon of porous membranes.

[0141]FIG. 11 is a cross-sectional view of an aerosol delivery device ofthe invention having a multidose container and single ribbon having bothinterconnected low resistance filters and nozzles comprised of porousmembranes.

[0142] The aerosol delivery devices of the invention can also compriseadditional components such as, but not limited to, a monitor foranalyzing a patient's inspiratory flow (e.g., a flow sensor 31 as shownin FIG. 12 having tubes 35 and 36 connected to a pressure transducer 37,which tubes 35 and 36 communicate with the flow path 29 and whichpressure transducer is electrically connected to a microprocessor 26), aheating mechanism for adding energy to the air flow into which theaerosol particles are released (e.g., a heating mechanism 14 as shown inFIG. 12), means for measuring ambient temperature and humidity (e.g., ahygrometer 50 and thermometer 51 as shown in FIG. 12), screens toprevent undesirable particles in the environment from entering the flowpath (e.g., screens 32, 33, and 34 as shown in FIG. 12), and/or othercomponents that might enhance aerosol delivery and/or patient compliancewith an aerosol delivery regimen. The device can also comprisecomponents that provide or store information about a patient's aerosoldelivery regimen and compliance with such, the types and amounts of drugdelivered to a patient, and/or other information useful to the patientor attending physician. Devices suitable for aerosol delivery accordingto the invention (i.e., that can be adapted for use with a lowresistance filter and nozzle as described herein) are described in U.S.Pat. No. 5,544,646, issued Aug. 13, 1996; U.S. Pat. No. 5,497,763,issued Mar. 12, 1996; U.S. Pat. No. 5,855,562; PCT published applicationWO 96/13292, published May 9, 1996; and PCT published application WO9609846, published Apr. 4, 1996, each of which is incorporated herein byreference to describe and disclose such aerosol delivery devices.

[0143] Aerosolization as described herein can be carried out with adevice that obtains power from a plug-in source; however, the device ispreferably a self-contained, portable device that is battery powered.For example, the methodology of the invention can be carried out using aportable, hand-held, battery-powered device which uses a microprocessor(e.g, as the means for recording a characterization of the inspiratoryprofile) as per U.S. Pat. Nos. 5,404,871; 5,450,336; and 5,906,202,incorporated herein by reference. The microprocessor is programmed usingthe criteria described herein using the device, dosage units, and systemdisclosed in U.S. Pat. Nos. 5,709,202; 5,497,763; 5,544,646; and5,823,178, with modifications as described herein. Alternatively, themethodology of the invention can be carried out using a mechanical(nonelectronic) device. Those skilled in the art would recognize thatvarious components can be mechanically set to actuate at a giveninspiratory flow rate and at a given volume (e.g., a spinnable flywheelwhich rotates a given amount per a given volume).

[0144] An exemplary device 40 of the invention is shown in FIG. 12. Thedevice 40 is a hand held, self-contained, portable, breath-actuatedinhaler device 40 having a holder 20 with cylindrical side walls and ahand grip 21. The holder 20 is “loaded,” i.e., connected to a container1 that includes dosage units having liquid, flowable formulations ofpharmaceutically active drug or diagnostic agent therein. A plurality ofcontainers 1 (2 or more) are preferably linked together to form apackage 46. FIG. 13 is a cross-sectional view of a cassette 500 loadedinto a delivery device 40. The disposable package 46 is folded or woundinto the cassette 500 in a manner which makes it possible to move theindividual containers 1 into a formulation release position within thedevice 40. While the containers 1 are moved into position the cover 400is removed. Although it is possible to rewind any used portion of thepackage on a sprocket 70 and rewind the used cover 400 on a sprocket 85or randomly fold it into a compartment, it is also possible to dispensethe used portion outside of the cassette 500 and device 40 andimmediately dispose of such.

[0145] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, that the foregoing description as well as the examples whichfollow are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains.

[0146] All patents, patent applications, and publications mentionedherein are hereby incorporated by reference in their entirety.

EXAMPLES Example 1

[0147] Generation of Stepped Pores in Reduced-Pressure AerosolizationNozzles

[0148] Nozzles were prepared from thin-film polyimide (25 μm, KAPTON™Type 100H, DuPont de Nemours Co., Inc.) using an excimer laser. Beforedrilling the pores, the polyimide film was laminated to analuminum-polyethylene composite lid layer through comprising one or moredie-cut holes, each approximately 6 mm×1.5 mm. The laminate was held bya vacuum platen to a three axis stage.

[0149] A 7×48 array of holes in an area of 2.8 mm×0.5 mm was ablated inthe polyimide using 5X projection lens. A mask containing an array oftransparent areas of 125 μm in diameter was used to generate poreshaving an entrance diameter of 25 μm. About 40 pulses of an excimerlaser at 630 mJ/cm² were used to ablate a first step partially throughthe membrane, to a depth of about 15 μm, thereby forming the first porestep. Then the mask was moved to a different position having having UVtransparent areas of 20 μm to generate a second pore step in the pores,the second step having an entrance aperture of about 4 μm and an exitaperture of about 1.25 microns using about 65 pulses of the same laser.

[0150] A scanning electron micrograph image of an example of a two-steppore is shown in FIG. 3.

Example 2

[0151] Dosage Forms and Blister Packs

[0152] A polyimide-aluminum/polyethylene laminate was made, and a 7×48array of holes in a 2.8 mm×0.5 mm of the polyimide was formed asdescribed in Example 1. A section of laminate comprising one 7×48 arrayof holes is a single nozzle. To make a single dosage form, an Aclamblister layer filled with a formulation was heat-sealed to a singlenozzle. A single dosage form is shown in FIG. 6. A clamp was formedaround the blister and nozzle area. Application of 200 to 400 psi ofpressure to the dosage unit resulted in extrusion of the formulationfrom the blister, through the pores in the nozzle, whereby an aerosolwas formed. The time from initial application of pressure to aerosolformation was 1.5 seconds.

[0153] To make a blister pack comprising multiple dosage forms, apolyimide layer was laminated to an aluminum/polyethylene layer asdescribed in Example 1, where the aluminum/polyethylene composite lidlayer comprised a regular array of die-cut holes, each about 6 mm×1.5mm. Holes were drilled in the polyimide layer in each of the nozzleareas, as described in Example 1. An Aclam layer comprising a pluralityof blisters filled with liquid formulation was heat-sealed onto thelaminate, such that each nozzle area was juxtaposed to aformulation-filled blister, as shown in FIGS. 7 and 8.

Example 3

[0154] Formation of Pores Using Grayscale Process

[0155] A mask comprising a first, inner circular area which allowed 100%transmission of energy, a second, circular area surrounding andconcentric with the first area which comprised a density of opaque dotssuch as to allow 50% transmission of energy, was used to generate poresin a 25 μm thick KAPTON™ film. The first circular area had a diameter of6 μm, while the second area had a diameter of 25 μm. An excimer laser asdescribed in Example 1 was used. 120 pulses of an excimer laser at anenergy density of 570 mJ/cm² was directed onto the mask and through thefilm until pores were formed. A cross-sectional image of a pore formedin this manner is depicted in FIG. 4.

[0156] Two types of Grayscale nozzles were made in this manner. Type Iand Type II nozzles comprise pores having inner circle entrancediameters of 6 μm and 5 μm, respectively, as shown in Table 1. TABLE 1Inner circle Energy Diameter Density No. Focus μm mJ/cm² Pulses μm TypeI 6 570 120 0 Type II 5 660 120 0

[0157] When used in an aerosolization packet, as described in Example 2,grayscale nozzles generated aerosols having an average particle size of2.5 μm, and an emitted dose of about 65% (i.e., the percentage of theformulation held in the container which was emitted). These parameters,i.e., average particle size and emitted dose, were the same as thoseobtained using a “standard” nozzle. A “standard” nozzle has pores withan entrance diameter of about 6 μand an exit diameter of about 1 μm, asshown in FIG. 1, but otherwise is the same as the grayscale nozzle.

[0158] The Type I and Type II grayscale nozzles, as well as a standardnozzle, were analyzed for extrusion pressure required to generate anaerosol having average particle size of 2.5 μm, and an emitted dose ofabout 65%. The pressure required to generate such an aerosol using astandard nozzle is about 650 psi. A total of 70 individual packetscomprising of Type I or Type II grayscale nozzles were analyzed. Theaverage extrusion pressure required to generate an aerosol with theabove-mentioned parameters was 297.14 psi for the Type I, and 358.45 psifor the Type II grayscale nozzle.

Example 4

[0159] Formation of Pores by Dithering

[0160] A laser beam with an entrance aperture of 30 nm at the mask wasdisplaced from the origin by 10 μm. The beam was rotated during theablation process, thereby directing the laser to etch the membrane in aroughly circular pattern, through the thickness of the membrane, in adecreasing radius with each successive step for several steps to etchthe polyimide membrane (25 μm thick), forming pores having across-sectional profile as shown in FIG. 5.

[0161] While the present invention has been described with reference tothe specific embodiments thereof, it should be understood by thoseskilled in the art that various changes may be made and equivalents maybe substituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

What is claimed is:
 1. A nozzle for aerosolizing a flowable liquidformulation for delivery to a patient, comprising: a sheet of flexiblemembrane material having an entrance side to which said formulation isapplied under a pressure, an exit side from which aerosol is released,and a nozzle area, which nozzle area has a plurality of pores thereinthrough which said formulation is extruded, each of said pores having anentrance aperture and an exit aperture having a pore entrance aperturesize and a pore exit aperture size, wherein the ratio of pore entranceaperture size to pore exit aperture size is at least about 10:1.
 2. Theaerosolization nozzle of claim 1, wherein the ratio of pore entranceaperture size to pore exit aperture size is at least about 15:1.
 3. Theaerosolization nozzle of claim 1, wherein the ratio of pore entranceaperture size to pore exit aperture size is at least about 25:1.
 4. Theaerosolization nozzle of claim 1, wherein each of the pores comprisestwo or more pore steps, each pore step having a pore step entranceaperture size and a pore step exit aperture size, wherein the entranceaperture size of each successive pore step from the entrance side to theexit side of the membrane is about 20 to about 90% of the exit aperturesize of the preceding, entrance-proximal, pore step.
 5. Theaerosolization nozzle of claim 1, wherein the pores are tapered inconfiguration, gradually narrowing from the entrance aperture to theexit aperture.
 6. The aerosolization nozzle of claim 1, wherein saidpores are positioned at a distance of about 30 to about 70 μm apart fromone another, wherein said pores in said nozzle area are at a density ofleast about 100 pores per square millimeter, and further wherein themembrane material has a thickness in the range of about 10 to 100micrometers.
 7. The aerosolization nozzle of claim 1, wherein said poreshave an exit aperture diameter in the range of about 0.5 μm to about 50μm, wherein said pores in said nozzle area are at a density of leastabout 200 pores per square millimeter, and further wherein the membranematerial has a thickness in the range of about 20 to 30 microns.
 8. Thenozzle of claim 1, further comprising: a removable cover sheetdetachably connected to the nozzle area.
 9. The nozzle of claim 1,wherein the exit apertures are regularly spaced in the nozzle area inrows, and further wherein the flexible membrane material is a polymerselected from the group consisting of polyimides, polyether imides,polyethers, polyesters, polyethylene and polycarbonates.
 10. The nozzleof claim 1, wherein said membrane comprises a plurality of nozzle areas.11. A container for aerosolizing a flowable liquid formulation fordelivery to a patient, comprising: (a) a sheet of flexible membranematerial having an entrance side to which said formulation is appliedunder a pressure, an exit side from which aerosol is released, and anozzle area, which nozzle area has a plurality of pores therein throughwhich said formulation is extruded, each of said pores having an exitaperture and an entrance aperture having a pore entrance aperture sizeand a pore exit aperture size, wherein the ratio of pore entranceaperture size to pore exit aperture size is at least about 10:1; (b)container walls connected to the sheet wherein a wall is collapsible bythe application of a force; and (c) a liquid formulation held within thecontainer walls.
 12. The container of claim 11, characterized such thata force of about 500 pounds per square inch (psi) or less collapses thecontainer and forces the formulation out of pores of the membrane andaerosolizes the formulation in 2 seconds or less.
 13. The container ofclaim 12, characterized such that a force of less than 400 psi isrequired.
 14. The container of claim 13, characterized such that a forceof 200 psi or greater is required.
 15. A disposable containercomprising: (a) at least one wall which is collapsible by theapplication of a force and having at least one opening, wherein saidopening leads to an open channel having an end; (b) a nozzle positionedat the end of the open channel, said nozzle comprising: a sheet offlexible membrane material having an entrance side to which saidformulation is applied under a pressure, an exit side from which aerosolis released, and a nozzle area, which nozzle area has a plurality ofpores therein through which said formulation is extruded, each of saidpores having an exit aperture and an entrance aperture having a poreentrance aperture size and a pore exit aperture size, wherein the ratioof pore entrance aperture size to pore exit aperture size is at leastabout 10:1; and (c) formulation in an amount of 100 milliliters or lessin the container.
 16. The disposable container of claim 15, wherein saidopen channel comprises a seal which is peeled open upon application of aforce exerted upon the collapsible wall.
 17. A disposable packagecomprising a plurality of the containers of claim
 15. 18. An aerosoldelivery device comprising: a device for holding the container of claim15; a mechanism for forcing the formulation through the nozzle.
 19. Amethod of producing a porous membrane, comprising the steps of:directing laser energy onto an entrance surface of a membrane andcontinuing to direct the energy until the laser has created a porehaving an entrance aperture and an exit aperture having a pore entranceaperture size and a pore exit aperture size, wherein the ratio of poreentrance aperture size to pore exit aperture size is at least about10:1, and repeating the directing a plurality of times, creating porespositioned at a distance of about 30 to about 70 micrometers apart,creating a porous membrane with a pore density of at least about 100pores per square millimeter.
 20. The method of claim 19, wherein therepeating is carried out by repositioning the laser energy for eachdirecting step.
 21. The method of claim 19, wherein the repeating iscarried out by repositioning the membrane for each directing step. 22.The method of claim 19, wherein the pore is formed by a process selectedfrom the group consisting of a multi-step process, a grayscale process,and a dithering process, wherein the membrane is comprised of apolymeric organic material, and wherein the membrane has a thickness ina range of from about 10 microns to about 100 microns.
 23. The method ofclaim 19, wherein the laser source is a UV excimer laser having awavelength of from about 150 nm to about 360 nm.
 24. The method of claim23, wherein the excimer energy density is from about 300 to about 800mJ/cm².
 25. The method of claim 19, wherein the membrane is comprised ofa material selected from the group consisting of polycarbonates,polyimides, polyethers, polyether imides, polyethylene and polyesters.26. A method of making an aerosolization container, comprising:providing a container comprising at least one wall which is collapsibleby the application of a force and having at least one opening, whereinsaid opening leads to an open channel having an end, said containercomprising formulation in an amount of 100 milliliters or less; andpositioning a nozzle according to claim 1 at the end of said channel,wherein said container is characterized such that a force of less in arange of about 200 psi to about 500 psi collapses the container, forcesthe formulation out of the pores in the nozzle, and aerosolizes theformulation in 2 seconds or less.
 27. A method of making an aerosoldelivery device, comprising producing a membrane having a plurality ofpores, wherein each of said pores has an entrance aperture size and anexit aperture size, and wherein the ratio of said entrance aperture sizeto said exit aperture size is at least about 10:1; and incorporating themembrane into an aerosol delivery device.